Muscular dystrophy refers to a group of genetic muscle diseases that causes weakening and wasting of the muscles. Generally, muscular dystrophies are characterized by progressive skeletal muscle weakness, defects in muscle proteins, and the death of muscle cells and tissue. The most common forms of muscular dystrophies include Duchenne, Becker, limb girdle, congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss. Of these, Duchenne muscular dystrophy (DMD) is the most common form affecting 1 in every 3,500 live male births. Becker muscular dystrophy (BMD) is a milder form of the disease.
Deficiency of dystrophin in dystrophic muscles results in loss of a large transmembrane protein complex, named dystrophin sarcolemma integrity. The “dystrophin-glycoprotein complex” (DGC) helps anchor the structural skeleton within the muscle cells, through the outer membrane of each cell, to the tissue framework that surrounds each cell.
Many signaling molecules, such as neuronal nitric oxide synthase (nNOS), associate with DGC. Loss of DGC in dystrophic muscle contributes to DMD pathogenesis. NO is an important regulatory signal for a large number of physiological and pathophysiological processes in the body. NO is produced by nNOS in the muscle. Without dystrophin, the membrane associated nNOS is not properly anchored to the sarcolemma and is instead mislocalized to the cytoplasm. This mislocalization results in decreased nNOS and NO levels. The reduction of nNOS and NO may lead to impaired skeletal muscle contraction, vascular dilation, and muscle damage.
Muscle tissue in adult vertebrates regenerates from reserve cells or stem cells or inactive myoblasts called satellite cells. Satellite cells are distributed throughout muscle tissue in close juxtaposition to muscle fibers, and are mitotically quiescent in adult muscle when injury, disease or muscle growth is absent. Following muscle fiber injury or during the process of recovery from disease, satellite cells re-activate and re-enter the cell cycle. Once activated, the satellite cells proliferate and the daughter cells (progeny cells termed myoblasts) either 1) fuse with existing multinucleated muscle fibers to contribute new nuclei that support muscle growth or regeneration, or 2) fuse with one another to form a new length of multinucleated muscle fiber called a myotube. Satellite cells of normal skeletal muscle provide a constant and renewable source of myogenic precursor cells which allows for skeletal muscle repair and regeneration throughout mammalian life.
NO mediates activation of satellite cells to enter the cell cycle. Such cycling provides new precursor cells for the skeletal muscle growth and muscle repair following injury or disease. Reduced NO production impairs muscle regeneration in normal muscle and exacerbates muscular dystrophy. Accordingly, developing a system to deliver NO to skeletal muscle and thereby manipulate the regulation of satellite cell activation has the potential to promote normal function in injured muscle tissue and possibly be used to treat neuromuscular disease.